Adult tissue stem cells including hematopoietic stem cells (HSC) are unique and rare cells responsible for regeneration of different tissues: blood, muscles, hair follicles, skin keratinocytes, pancreatic and neural cells (Orlic et al. 2001, Krause et al. 2001). Stem cell transplantation has been tested in clinical trials for tissue regeneration with a various but low degree of success. This is due to the fact that even after enrichment with the most up-to-date approaches, the resulting HSC populations are not homogeneous. A large proportion of cells may still have no HSC potential, molecular heterogeneity within different HSC subsets and other uncertainties make cell transplantation less feasible for tissue regeneration than HSC mobilization.
Primitive stem cells exhibit differential motility responses to the chemokine, stromal derived factor-1 (SDF-1) and lysophospholipid mediator sphingosine-1-phosphate (S1P) recently found to play a critical role in stem cell mobilization. Mobilization of stem cells from bone marrow into peripheral blood prior to harvesting is currently being used in clinical settings of allogeneic stem cell transplantation instead of bone marrow. The most common mobilizing agent for clinical uses is granulocyte colony stimulating factor (G-CSF). Other molecules have mobilizing effect on bone marrow cells (AMD3100, IL8, GM-CSF and others) their effect is shown to be indirect and not stem cell specific.
G-CSF, for example, acts on mature bone marrow cells; cells release proteases cleaving the adhesion factors responsible for the retention of cells in bone marrow. AMD3100, the CXCR4 inhibitor, approved recently for stem cell mobilization induces a more specific mobilization of cells into the circulation than G-CSF via disruption of the CXCR4-SDF1 interaction of bone marrow cells with their microenvironment; not only stem cells, but their immature progenitors and even malignant cells in Multiple Myeloma and Acute Promyelocytic leukemia express CXCR4 and therefore migrate into peripheral blood. (Kareem, et al. 2009).
Thus, all current drugs affect multiple cell populations, releasing into circulation high numbers of cells and causing changes in the bone marrow microenvironment. Therefore, these approaches cannot be used for multiple rounds of stem cell mobilization for tissue regeneration. Furthermore, both G-CSF and AMD3100, while mobilizing cells that can promote tissue repair, can also impair homing of mobilized stem and progenitor cells to sites of tissue damage, AMD3100 by blocking CXCR4 (Dai et al., 2010), the receptor for SDF-1, a primary chemotactic factor released by injured tissues, and G-CSF by cleaving CXCR4 (Honold, et al., 2006).
Under homeostatic conditions many physiological mechanisms including stem cell mobilization are found to be controlled by circadian oscillations; maximal mobilization of HSC into blood stream was found in mice at 5 hr after the onset of light with a reversed circadian HSC mobilization time (early night) demonstrated for human (Lucas, et al. 2008).
A stem-cell-specific mechanism increasing physiological level of cell mobilization is required for tissue regeneration and a drug that can be applied for multiple rounds of mobilization i.e. repeatedly causing stem cell egress from bone marrow without side effects and without impairing CXCR4-mediated homing of mobilized cells to damaged tissues is needed.